The present invention relates to vinylogous hydroxamic acids, processes for their manufacture, pharmaceutical preparations containing them, and their use in the treatment of various disorders.
Inflammatory diseases are a widespread cause of human suffering and loss of function. Additionally, the treatment of patients with these diseases represents a very large expense in terms of money, facilities and personnel. The incidence of many such diseases is expected to rise in the future as life expectancy and the median age of the population continue to increase.
Inflammatory diseases are known which affect many diverse tissues and organs in the body. Examples of diseases in which the inflammation is most apparent in the joints and related connective tissue are osteoarthritis, rheumatoid arthritis, tendonitis, bursitis, and the like. These diseases are most often treated with nonsteroidal anti-inflammatory agents such as aspirin, ibuprofen, and piroxicam, or with anti-inflammatory glucocorticosteroids. However, these treatments suffer either from a lack of efficacy in completely controlling the disease process, or from unacceptable toxic side effects.
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators of inflammation, the leukotrienes (LTs).
The naturally occurring leukotrienes derived from arachidonic acid are among the most potent in vivo regulators of biological activity known, showing their effects at sub-nanogram levels. They are released from many different cells, following immunologic or non-immunologic stimulation. A wide variety of biological effects are associated with the leukotrienes. Unfortunately, many of these biological effects are associated with the painful symptoms of inflammatory diseases, including asthma, arthritis, and allergic reactions. The peptidic leukotrienes, represented by LTC.sub.4, LTD.sub.4, and LTE.sub.4, are potent spasmogens, with 1000 times the activity of histamine. Inhaled LTC.sub.4 causes the immediate development of symptoms resembling those of an asthmatic attack. LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They have also been found in the synovial fluid of rheumatoid arthritis patients. Leukotrienes have also been implicated as important mediators in allergic rhinitis, psoriasis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, and ischemia induced by myocardial injury among others. British Medical Bulletin (1983), Vol. 39, No. 3, pp. 249-254, generally discusses the pharmacology and pathophysiology of leukotriene B.sub.4. The biological activity of the LTs has been reviewed by Lewis and Austen (J. Clinical Invest., 1984, 73, 889) and by Sirois (Adv. Lipid Res., 1985, 21, 78). A compound capable of selectively inhibiting 5-lipoxygenase while having weaker inhibitory effects on the cyclooxygenase enzyme is beneficial by preventing the formation of inflammatory and bronchioconstrictor mediators while having little inhibitory effect on protective prostaglandins in the stomach or on the bronchodilatory cyclooxygenase products, for example, prostacyclin. This may therefore be of use in maintaining the integrity of the gastrointestinal mucosa.
Thus, lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. Blocking these enzymes interrupts the biochemical pathways believed to be involved in these disease states.
U.S. Pat. Nos. 4,769,461; 4,897,422; 4,623,661; 4,822,811 4,769,387 and 4,820,828; U.S. Patent application number 119,926 (Nov. 13, 1987) and European patent application number 0,279,263 (Aug. 24, 1988) disclose the anti-inflammatory activity and 5-lipoxygenase inhibitory activity of simple hydroxamic acids with the structure: ##STR1## wherein A is a covalent bond or C.sub.1 to C.sub.6 alkylene or C.sub.2 to C.sub.6 alkenylene.
R.sub.1 is H, C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, or NR.sub.2 R.sub.3, wherein R.sub.2 and R.sub.3 are independently selected from H, C.sub.1 to C.sub.4 alkyl and hydroxyl, but R.sub.2 and R.sub.3 are not simultaneously hydroxyl.
X is O, S, SO.sub.2, or NR.sub.4, wherein R.sub.4 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoyl, or aroyl.
A is selected from C.sub.1 to C.sub.6 alkylene or C.sub.2 to C.sub.6 alkenylene.
n is 0 to 5.
Y is selected independently at each occurrence from H, halogen, OH, CN, halosubstituted alkyl, C.sub.1 to C.sub.12 alkyl, C.sub.2 to C.sub.12 alkenyl, C.sub.1 to C.sub.12 alkoxy, C.sub.3 to C.sub.8 cycloalkyl, aryl, aryloxy, aroyl, C.sub.1 to C.sub.12 aryalkyl, C.sub.1 to C.sub.12 arylalkenyl, C.sub.1 to C.sub.12 arylalkoxy, C.sub.1 to C.sub.12 arylthioalkoxy, and substituted derivatives for aryl, aryloxy, aroyl, C.sub.1 to C.sub.12 aryalkyl, C.sub.1 to C.sub.12 arylalkenyl, C.sub.1 to C.sub.12 arylalkoxy, C.sub.1 to C.sub.12 arylthioalkoxy, wherein substituents are selected from halo, nitro, cyano, C.sub.1 to C.sub.12 alkyl, alkoxy, and halosubstituted alkyl.
M is H, a pharmaceutically acceptable cation, aroyl, or C.sub.1 to C.sub.12 alkoyl.
R.sub.5 is R.sub.1 is phenyl [substituted 1 to 3 with Br, Cl, F, I, CF.sub.3, alkyl C.sub.1 to C.sub.14, NO.sub.2, CN, OR.sub.5, CHO, CH.sub.2 OR.sub.5, CO.sub.2 R.sub.5, COR.sub.6, phenyl, pyridyl (2, 3, 4), 2 or 3 thienyl, 2 or 3 furyl, SO.sub.3 H, S(O).sub.o R.sub.5 (o=0 to 2), or SO.sub.2 N(R.sub.2)2], naphthyl, 2, 3, or .sub.4 -pyridyl, 2 or 3 furyl, 2 or 3 thienyl, Y, alkyl (C.sub.1 to C.sub.14), or cycloalkyl of 3 to 6, trinuclear aromatic, or ##STR2## Compounds having these structures have also been described by Summers et al., J. Med. Chem., 1987, 30, 2121; 1987, 30, 574; 1988, 31, 3; and 1988, 31, 1960; also by Huang et al., J. Med. Chem. 1989, 32, 1836; and by Jackson et al., J. Med. Chem. 1988, 31, 499.
U.S. Pat. Nos. .sub.4,769,461 and 4,772,703 disclose the anti-inflammatory activity of simple hydroxamic acids with the structure: ##STR3## wherein W is a covalent bond, O, S, NR.sub.2, CH(OH), C(O), or NR.sub.2 C(O).
X is N or CR.sub.2.
Y is O, S, NR.sub.2, or C(R.sub.2).sub.2 when n=0, or N or CR.sub.2 when n=1.
Z is CH.sub.2 O, CH.sub.2 S, CH.sub.2 N(R.sub.2), O, S, N(R.sub.2), C(O), C(O)NR.sub.2, CH(R.sub.2)CH(R.sub.2), C(R.sub.2).dbd.C(R.sub.2), or C.intg.C.
R.sub.1 is H, lower alkyl, CF.sub.3, NO.sub.2, OH, lower alkoxy, SH, lower alkylthio, or halogen.
R.sub.2 is H or lower alkyl.
n is 0 to 1.
m is 1 to 6 with the proviso that m is 0 to 5 when W represents a covalent bond.
U.S. Pat. Nos. 4,761,403 and 4,757,078 disclose the anti-inflammatory activity and 5-lipoxygenase inhibitory activity of cyclic hydroxamic acids with the structure: ##STR4## wherein R.sub.1 through R.sub.5 are independently selected from H, C.sub.1 to C.sub.12 alkyl, C.sub.1 to C.sub.12 alkoxy, C.sub.1 to C.sub.8 carbalkoxy, C.sub.6 or C.sub.12 aryl, NO.sub.2, OH, halogen, or where R.sub.1 to R.sub.2, R.sub.3 to R.sub.4, or R.sub.4 to R.sub.5 form an aromatic fused ring.
M is a pharmaceutically acceptable cation, tri-C.sub.1 to C.sub.6 -alkylsilyl or C.sub.1 to C.sub.12 alkyl or acyl.
Sarlo et al. describe the preparation and some reactions of 1-phenyl-2-phenyl-3-(N-hydroxy-N-phenyl)-2-propene-1-one in J. Chem. Soc. Perkin 1, 1978, 1113.
Padwa et al., J. Oro. Chem. 1986, 51, 3127, describe the synthesis and thermal cyclization reactions of ##STR5##
Woodward et al. describe the preparation of 1-phenyl-3-(N-hydroxy-N-phenyl)-2-propene-1-one and 1-(3'-hydroxysulfonyl)phenyl-2-phenyl-3-(N-hydroxy-N-phenyl)-2-propene-1-o ne in J. Oro. Chem., 1967, 14, 388.
Lang et al., J. Heterocyclic Chem., 1977, 14, 345, describe the synthesis of ##STR6##
None of the above-described references disclose the compounds of the present invention or suggest that such compounds would possess activity as anti-inflammatory agents.